The negative inotropic effect of general anesthetics is appreciable for the potent agents such as halothane and enflurane. It can result in dangerous depression of circulatory function in patients with cardiovascular disease. Antagonism of this effect with the presently used positive inotropic drugs is incomplete, often inadequate, and sometimes associated with additional undesireable phenomena such as cardiac arrhythmias. A full understanding of the mechanism which underlies the negative inotropic action of anesthetics, though presently not available, would aid materially in the development of rational methods for offsetting this untoward effect. The specific aim of the proposed research is to quantitatively evaluate the effect of halothane, enflurane, isoflurane, and the intravenous agent thiopental on the steps in excitation-contraction coupling which lead to the intracellular release of activator CA++. Attention will be focused on the effects of these anesthetics on the transsarcolemmal influx of CA++, and on th CA++ released from intracellular storage sites. Information will be obtained from isolated papillary muscles (rat, rabbit, cat hearts). It is expected that the knowledge gained from these studies will suggest which, if any, of several new cardiotonic drugs, known to act via mechanisms different from catecholamines or cardiac glycosides, will prove especially useful for reversing anesthetic-induced myocardial depression.